Polymeric, degradable drug-eluting stents and coatings

ABSTRACT

Absorbable stents and absorbable stent coatings have been developed with improved properties. These devices preferably comprise biocompatible copolymers or homopolymers of 4-hydroxybutyrate, and optionally poly-L-lactic acid and other absorbable polymers and additives. Compositions of these materials can be used to make absorbable stents that provide advantageous radial strengths, resistance to recoil and creep, can be plastically expanded on a balloon catheter, and can be deployed rapidly in vivo. Stent coatings derived from these materials provide biocompatible, uniform coatings that are ductile, and can be expanded without the coating cracking and/or delaminating and can be used as a coating matrix for drug incorporation.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. Ser. No.11/671,632, filed on Feb. 6, 2007, now U.S. Pat. No. 7,618,448, whichclaims priority to U.S. Ser. No. 60/747,144, filed May 12, 2006, U.S.Ser. No. 60/765,840, filed Feb. 7, 2006, and U.S. Ser. No. 60/765,808,filed Feb. 7, 2006.

FIELD OF THE INVENTION

The present invention generally relates to absorbable polymercompositions that can be used to prepare absorbable stents, andabsorbable stent coatings.

BACKGROUND OF THE INVENTION

Stents are currently used in a range of medical applications normally toprevent re-occlusion of a vessel after a procedure to dilate the vessel.Examples include cardiovascular, urology, and gastroenterology stents,with the former being by far the largest market. Generally, stents aremade from permanent materials, such as metal alloys or non-absorbablethermoplastics, and can additionally incorporate special coatings anddrugs to improve their performance in vivo. These coatings, for example,include a number of polymer coating materials for metallic stents, aswell as a variety of active agents, such as agents that areanti-inflammatory or immunomodulators, antiproliferative agents, agentswhich affect migration and extracellular matrix production, agents whichaffect platelet deposition or formation of thrombis, and agents thatpromote vascular healing and re-endothelialization. Notably the coatingsof currently marketed stents are made from permanent materials.

While the incorporation of certain active agents in coatings on thesurfaces of coronary metal stents has been demonstrated to retardrestenosis, it has been reported that the polymer coatings that are leftafter elution of the drug can present a serious risk of late thrombosis(Virmani, R et al., Coron Artery Dis. 2004; 15(6):313-8). It has alsobeen reported that the polymeric coating materials of drug-elutingstents may cause hypersensitivity reactions in the patient treated withsuch coated stents (Nebeker, J. R. et al., J Am Coll Cardiol 2006;47:175-81). Thus, there is a need to develop new stent coating materialsthat can be used to deliver drugs without the risk of late thrombosisand hypersensitivity reactions.

Furthermore, although permanent metal stents are used widely in coronarystenting applications, and their use in peripheral stenting is growingrapidly, there remain several drawbacks to the use of permanentmaterials to manufacture these stents (Colombo, A et al., Circulation.2000 25; 102(4):371-3, Erne, P. et al., Cardiovasc Intervent Radiol.2005). First, metal stents are not compatible with certain methods ofmedical imaging, such as MRI and CT scanning systems. Second, metalstents can cause complications if the patient subsequently needscoronary artery bypass surgery, or other surgical intervention,requiring manipulation of a stented vessel. Third, the use of permanentstents can result in long-term compliance mismatches between the metalstent and the stented vessel, and fourth, in certain peripheralapplications, catastrophic failure of metal stent struts has beenreported.

It should also be noted that permanent stents used in urologyapplications to temporarily relieve obstruction in a variety of benign,malignant, and post-traumatic vessel conditions are prone to rapidencrustation (Shaw G. L. et al., Urol Res. 2005 February; 33(1):17-22).Such encrustation often necessitates removal of the stent. Removal,however, requires an additional procedure, and can be difficult andpainful because of tissue in-growth. The use of a degradable implantwould eliminate this clinical problem.

To address the disadvantages associated with the use of permanentmaterials in stents and stent coatings, there have been several reportsdescribing the use of absorbable materials to make stents and stentcoatings. U.S. Pat. Nos. 5,059,211 and 5,306,286 to Stack et at.describe the use of absorbable materials to make stents. Stack, however,does not describe which specific absorbable materials a person skilledin the art would use to make an absorbable stent, or the propertiesnecessary to make such stents.

U.S. Pat. No. 5,935,506 to Schmitz et al. describes a method tomanufacture an absorbable stent from poly-3-hydroxybutyrate (P3HB).

U.S. Pat. No. 6,045,568 to Igaki et al. describes absorbable stentsmanufactured from knitting yarns of polylactic acid (PLA), polyglycolicacid (PGA), polyglactin (P(GA-co-LA)), polydioxanone (PDS),polyglyconate (a block co-polymer of glycolic acid and trimethylenecarbonate, P(GA-co-TMC)), and a copolymer of glycolic acid or lacticacid with ε-caprolactone (P(GA-co-CL) or P(LA-co-CL)).

Laaksovirta et al. describe a self-expandable, biodegradable,self-reinforced stent from P(GA-co-LA) for use in urethral applications(J Urol. 2003 Aug; 170(2 Pt 1):468-71).

The potential use of polyanhydride and polyorthoester polymers tomanufacture absorbable stents has also been described by Tanguay, J. F.et al. Current Status of Biodegradable Stents, Cardiology Clinics,12:699-713 (1994).

WO 98/51812 to Williams et al. discloses methods to remove pyrogens frompolyhydroxyalkanoates, and the fabrication of stents with thesedepyrogenated materials. WO 99/32536 to Martin et al. and WO 00/56376 toWilliams et al. disclose methods to prepare polyhydroxyalkanoates withcontrolled degradation rates, and the fabrication of stents with thesematerials.

Van der Giessen et al. (Marked Inflammatory Sequelac to Implantation ofBiodegradable and Nonbiodegradable Polymers in Porcine CoronaryArteries, Circulation, 94:1690-1697 (1996)) evaluated coatings of acopolymer of glycolic acid and lactic acid (P(GA-co-LA)),polycaprolactone (PCL), poly-3-hydroxybutyrate-co-3-hydroxyvalerate(P(3HB-co-3HV), a polyorthoester, and a polyethyleneoxide-polybutyleneterephthalate on metal stents, and reported that the coatings inducedmarked inflammatory reactions within the coronary artery.

Despite some progress towards the development of absorbable stents andstent coatings, there is currently no coronary or peripheral stentdevice comprising an absorbable material approved for general sale inthe United States or Europe. This is partly because of the highlydemanding requirements of an absorbable material used for medicalstenting applications and the shortcomings of the currently availablematerials. Further improvements to existing materials that areconsidered desirable, or required, include the following elements: (i)an absorbable stent or stent coating that is biocompatible, does notcreate a risk of late stage thrombosis, and provides long-term vesselpatency; (ii) an absorbable stent that has sufficient radial strength(or hoop strength) to prevent the collapse of the vessel wall or stent;(iii) an absorbable polymer composition that when processed into a stentor stent coating can be expanded in vivo, from a suitably low profileform to the desired diameter without surface or strut cracking orsimilar types of mechanical failure; (iv) an absorbable stent orpermanent stent coated with an absorbable polymer that can be dilatedsufficiently fast in vivo to allow deployment of the stent without riskto the patient, and using a reasonable inflation pressure if the stentis delivered using a balloon catheter; (v) an absorbable stent that doesnot recoil significantly after deployment; (vi) an absorbable stent thatis sufficiently resistant to creep to be effective; (vii) an absorbablestent with strut thicknesses that are relatively low in profile once thestent is implanted, and with edges that are smooth; (viii) an absorbablestent coating that can be applied in a uniform manner, without defectssuch as web formation between struts, and a method for such application;(ix) an absorbable stent, and/or a stent coated with an absorbablematerial, where the struts are not susceptible to fracture afterimplantation, and the risk of vessel perforation is eliminated; (x) anabsorbable stent that does not interfere with medical scanning systems,such as MRI and CT; (xi) an absorbable stent, and a stent coated with anabsorbable material, that protects against an inflammatory response,limits smooth muscle cell proliferation, and neointimal hyperplasiaafter implantation, stimulates positive remodeling of the vessel wall,and eliminates long-term compliance mismatches between the stent and thevessel wall; (xii) an absorbable stent, and/or a stent coated with anabsorbable material, that is sufficiently flexible to allow delivery tothe desired location without strut fracture or kinking, which canconform to the shape of the affected body lumen; (xiii) an absorbablestent that contains a contrast agent, radiopaque markers, or similarmaterial that allows the stent to be imaged using conventional scanningtechniques; (xiv) an absorbable coating that adheres sufficientlystrongly to a metal stent, maintains its integrity following stentexpansion and does not delaminate; (xv) an absorbable stent and a coatedpermanent stent that can be loaded with one or more drugs or co-drugs(for example, on the inside or surface of the stent or coating) toimprove the performance of the stent by controlled delivery of thedrug(s), including agents that are anti-inflammatory orimmunomodulators, antiproliferative agents, drugs which affect migrationand extracellular matrix production, drugs which affect plateletdeposition or formation of thrombis, and drugs that promote vascularhealing and re-endothelialization, and that also allow larger drugloadings; (xvi) an absorbable stent and/or a stent coated with anabsorbable material that can be mounted onto a catheter, andsubsequently delivered in vivo without causing damage to the stent;(xvii) an absorbable stent, and an absorbable coating on a stent, thatis absorbed in vivo over a time period that allows positive remodelingof the vessel wall, does not prematurely fail due to fatigue, andresults in long-term vessel patency; (xviii) an absorbable stent thatdoes not shorten in an undesirable manner upon expansion and deployment;(xix) an absorbable stent or permanent stent coated with an absorbablematerial that can be sterilized without detrimental loss of properties,for example, by irradiation or exposure to ethylene oxide; (xx) anabsorbable stent and a coated metal stent that can be loaded with one ormore drugs to improve the performance of the stent by controlleddelivery of the drug(s), where the method of polymer degradation (e.g.surface erosion or bulk degradation) allows for delivery of large drugssuch as proteins; (xxi) an absorbable stent and a coated permanent stentthat can be loaded with one or more drugs to improve the performance ofthe stent by controlled delivery of the drug(s), where the low-aciditypolymer degradation products (of the stent or stent coating) allows fordelivery of large drugs such as proteins without drug denaturation;(xxii) an absorbable material for use in stents that has a glasstransition temperature below body temperature, a melt temperature above50° C., and a shelf-life of at least one to three years.

It is therefore an object of this invention to provide absorbablecompositions that can be used to develop improved absorbable stents, andabsorbable stent coatings.

It is another object of this invention to provide improved absorbablestents, and stents coated with absorbable materials.

It is a further object of this invention to provide methods forpreparing improved absorbable stents and stents coated with absorbablematerials.

It is a yet still further object of this invention to provide methodsfor the delivery of the absorbable stents and stents coated withabsorbable materials.

SUMMARY OF THE INVENTION

Absorbable compositions and stents, and absorbable coatings for stents,with improved properties and performance, and methods for making thesematerials and devices, have been developed. These compositions anddevices are preferably derived from a biocompatible homopolymer and/orcopolymer(s) of 4-hydroxybutyrate, and combinations (e.g., blends) ofthese materials with other absorbable materials. Absorbable stents aremost preferably derived from compositions comprising a homopolymer orcopolymer(s) of 4-hydroxybutyrate with a polymer of lactic acid, with orwithout plasticizers.

In one embodiment, the stent is a metallic stent coated with a basecoating containing a blend of poly-4-hydroxybutyrate (P(4HB)) andpoly(L-lactide) (PLLA) and optionally a top coat containing P(4HB). Inanother embodiment, the stent is a metallic stent coated with a basecoat containing a blend of P(4HB) and PLLA and optionally a top coathaving the same composition as the base coat. The base coat has athickness of about 10 microns to about 50 microns, more preferably fromabout 15 microns to about 25 microns. In one embodiment, the base coathas a thickness of about 20 microns, which corresponds to a drugconcentration of 2 μg/mm². The top coat has a thickness of about 10microns to about 40 microns, preferably from about 10 microns to 20microns. In one embodiment, the top coat has a thickness of about 15microns.

Different methods may be used to apply the absorbable stent coatings.Most preferably, the coatings are applied from solution by spraying.Different methods may be used to prepare the absorbable stents. Apreferred method comprises forming a tube by solution dipping orextrusion, injection molding or micro injection molding, and cutting thetube with a laser to form the stent. The stent may be used asmanufactured or expanded in vivo, for example, using an expandableballoon catheter.

The absorbable stent coatings provide devices with thin coatings on thestent struts, without the formation of web-like structures between thestruts, and stents that can be expanded quickly without the coatingcracking, delaminating, or losing its structural integrity. Theabsorbable stent coatings are biocompatible, degrade to less acidicmetabolites by mechanisms that include surface erosion (minimizing therisk of particulate breaking away from the stent surface), elongate upto 1,000% of their original length, adhere to the stent, can be mountedto a catheter and deployed without damage to the coating, degrade over aperiod of up to about one year, can be sterilized by irradiation ortreatment with ethylene oxide, and can be loaded or coated with drugsfor controlled release. The stents are flexible, and more compliant withthe vessel wall; have sufficient radial strength and strength retentionto permit positive remodeling for long-term patency; and have a radialrecoil of less than 10%, and more preferably less than 6%; can beexpanded rapidly in vivo, without cracking or other mechanical failure,preferably in less than five minutes, and more preferably in less thanone minute, using a balloon pressure of 4 to 16 bar, more preferably 8bar, and can be delivered to the desired location without strutfracture, kinking, or damage to the vessel wall; do not exhibit anysignificant creep at 100 mmHg for 7 days, do not shorten significantlyupon expansion; can be constructed with smooth strut edges with strutthicknesses of less than 300 μm, more preferably 160 μm or less forcoronary applications, and 250-270 μm for peripheral applications; cancontain contrast agents, radiopaque markers or similar material to allowthe imaging of the stent in vivo, and can also be loaded and/or coatedwith therapeutic, prophylactic or diagnostic agents, including, but notlimited to, agents that are anti-inflammatory or immunomodulators,antiproliferative agents, drugs which affect migration and extracellularmatrix production, drugs which affect platelet deposition or formationof thrombis, and drugs that promote vascular healing andre-endothelialization, at low or high drug loadings; can be sterilized,for example, by gamma-irradiation, electron-beam irradiation or ethyleneoxide. In the specific case of coronary applications, the absorbablecompositions can be used to prepare absorbable stents that can beexpanded in vivo from an inner diameter of approximately 1-1.4 mm to 3-4mm in about one minute. Larger absorbable stents can also be made foruse, for example, in peripheral and urology applications. A preferredinternal diameter for peripheral applications is 2.0 to 2.8 mm with awall thickness of 250-270 μm.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the chemical structure of poly-4-hydroxybutyrate (P4HB,TephaFLEX® biomaterial).

FIG. 2 shows some of the known biosynthetic pathways for the productionof P4HB. Pathway enzymes are: 1. Succinic semialdehyde dehydrogenase; 2.4-hydroxybutyrate dehydrogenase; 3. diol oxidoreductase; 4. aldehydedehydrogenase; 5. Coenzyme A transferase; and 6. PHA synthetase.

FIG. 3 is a graph showing the accelerated decrease of molecular weight(Mw) of a polymer blend material of high molecular weight PLLA and P4MBwith a mass ratio of 78:22% in comparison to pure PLLA as a function ofin vitro incubation time in Sorensen buffer (pH=7.4) at 37° C.

FIG. 4 is a graph showing the in vitro drug release profiles of metallicstents coated with the following different compositions of a P4HB matrixincorporated with the immunomodulator rapamycin as a base coat, andcoated with a top coat of pure P4HB as a diffusion barrier for retardeddrug release: stent 85:15-1 polymer/drug ratio 85:15 (w/w), base coatthickness=20 μm, no top coat; stent 85:15-2-polymer/drug ratio 85:15(w/w), base coat thickness=20 μm, top coat thickness=5 μm; stent85:15-3-polymer/drug ratio 85:15 (w/w), base coat thickness=20 μm, topcoat thickness=15 μm; stent 85:15-4-polymer/drug ratio 85:15 (w/w), basecoat thickness=10 μm, top coat thickness=10 μm.

FIG. 5 is a graph showing the in vitro drug release profiles of metallicstents coated with the following different compositions of a P4HB matrixincorporated with the immunomodulator rapamycin as a base coat, andcoated with a top coat of pure P4HB as a diffusion barrier for retardeddrug release: stent 40:60-1-polymer/drug ratio 40:60 (w/w), base coatthickness=5 μm, top coat thickness=10 μm; stent 70:30-1-polymer/drugratio 70:30 (w/w), base coat thickness=5 μm, top coat thickness=10 μm;stent 85:15-4-polymer/drug ratio 85:15 (w/w), base coat thickness=10 μm,top coat thickness=10 μm.

FIG. 6 is a graph showing the in vitro cumulative release of rapamycin(μg/mm) as a function of time (hours) from stents having a base coat of100/0 w/w P(4HB)/PLLA (♦), 70/30 w/w P(4MB)/PLLA (▴), 50/50 w/wP(4HB)/PLLA (●), and 30/70 P(4HB)/PLLA w/w (▪) and a top coat of P(4HB).

FIG. 7 is a graph showing the in vitro cumulative release of rapamycin(μg/mm) as a function of time (hours) from stents having a base coat of70/30 w/w P(4HB)/PLLA (▴), 50/50 w/w P(4HB)/PLLA (●), and 30/70P(4HB)/PLLA w/w (▪) and a top coat of having the same composition as thebase coat.

DETAILED DESCRIPTION OF THE INVENTION

Absorbable stents and stents coated with absorbable materials have beendeveloped that have improved properties.

I. Definitions

“Poly-4-hydroxybutyrate” as generally used herein means a homopolymercomprising 4-hydroxybutyrate units. It may be referred to herein as P4HBor TephaFLEX® biomaterial (manufactured by Tepha, Inc., Cambridge,Mass.).

“Copolymers of poly-4-hydroxybutyrate” as generally used herein meansany polymer comprising 4-hydroxybutyrate with one or more differenthydroxy acid units.

“Copolymers of lactic acid” as generally used herein means any polymercomprising lactic acid with one or more different hydroxy acid units.

“Molecular weight” as used herein, unless otherwise specified, refers tothe weight average molecular weight (Mw) as opposed to the numberaverage molecular weight (Mn).

“Blend” as generally used herein means a macroscopically homogeneousmixture of two or more different species of polymer.

“Absorbable” or “degradable” as generally used herein means the materialis broken down in the body and eventually eliminated from the body.

“Biocompatible” as generally used herein means the biological responseto the material or device is appropriate for the device's intendedapplication in vivo. Any metabolites of these materials should also bebiocompatible.

II. Compositions

A. Absorbable polymers

The stents and stent coatings may be formed from absorbable polymers,such as poly-4-hydroxybutyrate (P4HB), and copolymers thereof such aspoly-4-hydroxybutyrate-co-3-hydroxybutyrate (P(4HB-co-3HB)). In apreferred embodiment, the absorbable stents are formed from combinationsof P4HB and/or copolymers thereof, with a second absorbable material. Apreferred second absorbable material is a polyhydroxy acid, preferablypolylactic acid (PLA), and even more preferably poly-L-lactic acid(PLLA) (such as Resomer® L214 available from Boehringer Ingelheim).Copolymers of lactic acid may also be used as the second absorbablematerial, including copolymers with glycolic acid. Alternatively, thestents may coated with a base coating containing a blend of P(4HB) andPLLA. The top coat can be P(4HB) or a blend of P(4HB) and PLLA havingthe same composition as the base coat.

Tepha, Inc. of Cambridge, Mass. produces poly-4-hydroxybutyrate (P4HB)and copolymers thereof using transgenic fermentation methods.Poly-4-hydroxybutyrate is a strong, pliable thermoplastic polyester thatis produced by a fermentation process (see U.S. Pat. No. 6,548,569 toWilliams et al.). Despite its biosynthetic route, the structure of thepolyester is relatively simple (FIG. 1). The polymer belongs to a largerclass of materials called polyhydroxyalkanoates (PHAs) that are producedby numerous microorganisms (Steinbüchel, A. Polyhydroxyalkanoic acids,Biomaterials, 123-213 (1991); Steinbüchel A., et al. Diversity ofBacterial Polyhydroxyalkanoic Acids, FEMS Microbial Lett. 128:219-228(1995); and Doi, Y. Microbial Polyesters (1990)). In nature thesepolyesters are produced as storage granules inside cells, and serve toregulate energy metabolism. They are also of commercial interest becauseof their thermoplastic properties, and relative ease of production.Several biosynthetic routes are currently known for producing P4HB, asshown in FIG. 2. Chemical synthesis of P4HB has been attempted, but ithas not been possible to produce the polymer with a sufficiently highmolecular weight necessary for most applications (Hori, Y., et al.,Polymer 36:4703-4705 (1995)).

Tepha, Inc. (Cambridge, Mass.) produces P4MB and related copolymers formedical use, and has filed a Device Master File with the United StatesFood and Drug Administration (FDA) for P4HB. Related copolymers include4-hydroxybutyrate copolymerized with 3-hydroxybutyrate or glycolic acid(U.S. patent application publication number US 2003/0211131 by Martin &Skraly, U.S. Pat. No. 6,316,262 to Huisman et al., and U.S. Pat. No.6,323,010 to Skraly et a.). Tepha has also filed a Device Master Filewith the United States FDA for copolymers containing 3-hydroxybutyrateand 4-hydroxybutyrate. Methods to control molecular weight of PHApolymers are disclosed by U.S. Pat. No. 5,811,272 to Snell et al, andmethods to purify PHA polymers for medical use are disclosed by U.S.Pat. No. 6,245,537 to Williams et al. PHAs with degradation rates invivo of less than one year are disclosed by U.S. Pat. No. 6,548,569 toWilliams et al. and WO 99/32536 to Martin et al. Other applications ofPHAs are reviewed in Williams, S. F., et al., Polyesters, III, 4:91-127(2002), and other applications specific to P4HB are reviewed in Martinet al. Medical Applications of Poly-4-hydroxybutyrate: A Strong FlexibleAbsorbable Biomaterial, Biochem. Eng. J 16:97-105 (2003).

In one embodiment, the stent is a metallic stent coated with a base coatcontaining a blend of P(4HB), PLLA, and a therapeutic, prophylactic, ordiagnostic agent. The blend can contain from about 100% to about 30%P(4HB) w/w, for example, 100/0 P(4HB)/PLLA w/w, 95/5 P(4HB)/PLLA w/w,90/10 P(4HB)/PLLA w/w, 85/15 P(4HB)/PLLA w/w, 80/20 P(4HB)/PLLA w/w,75/25 P(4HB)/PLLA w/w, 70/30 P(4HB)/PLLA w/w, 65/35 P(4HB)/PLLA w/w,60/40 P(4HB)/PLLA w/w, 55/45 P(4HB)/PLLA w/w, 50/50 P(4HB)/PLLA w/w,45/55 P(4HB)/PLLA w/w, 40/60 P(4HB)/PLLA w/w, 35/65 P(4HB)/PLLA w/w, or30/70 P(4HB)/PLLA w/w. The stent can subsequently be coated with a topcoat containing P(4HB) or a blend of P(4HB) and PLLA having the samecomposition as the base coat.

The base coat has a thickness of about 10 microns to about 50 microns,more preferably from about 15 microns to about 25 microns. In oneembodiment, the base coat has a thickness of about 20 microns, whichcorresponds to a drug concentration of 2 μg/mm². In one embodiment, thebase coat has a thickness of about 20 microns, which corresponds to adrug concentration of 2 μg/mm². The top coat has a thickness of about 10microns to about 40 microns, preferably from about 10 microns to 20microns. In one embodiment, the top coat has a thickness of about 15microns. Stent coatings prepared from blends of P(4HB) and PLLA exhibitimproved surface integrity compared to coatings containing only PLLA.

B. Other Stent Components

i. Plasticizers

The absorbable material composition used to produce stents and stentcoatings may comprise other materials in addition to the polymersdescribed above. In a preferred method of the invention, a plasticizermay be introduced into the absorbable material prior to forming thestent or stenting coating. Preferred plasticizers are biocompatible. Aparticularly preferred plasticizer is triethylcitrate (TEC).

ii. Therapeutic, Prophylactic, and Diagnostic Agents

In addition to incorporating plasticizers into the absorbable material,it can be advantageous to incorporate one or more therapeutic,prophylactic or diagnostic agents (“agent”) into the stent, either byloading the agent(s) into the absorbable material prior to processing,and/or coating the surface of the stent with the agent(s). The rate ofrelease of agent may be controlled by a number of methods includingvarying the following: the ratio of the absorbable material to theagent, the molecular weight of the absorbable material, the compositionof the agent, the composition of the absorbable polymer, the coatingthickness, the number of coating layers and their relative thicknesses,and/or the agent concentration. Top coats of polymers and othermaterials, including absorbable polymers, may also be applied to activeagent coatings to control the rate of release. For example, P4HB(TephaFLEX® biomaterial from Tepha, Inc.) may be applied as a top coaton a metallic stent coated with P4HB containing an active agent, such asrapamycin (also known as Sirolimus), to retard the release of rapamycin.

Exemplary therapeutic agents include, but are not limited to, agentsthat are anti-inflammatory or immunomodulators, antiproliferativeagents, agents which affect migration and extracellular matrixproduction, agents which affect platelet deposition or formation ofthrombis, and agents that promote vascular healing andre-endothelialization, described in Tanguay et a. Current Status ofBiodegradable Stents, Cardiology Clinics, 12:699-713 (1994), J. E.Sousa, P. W. Serruys and M. A. Costa, Circulation 107 (2003) 2274 (PartI), 2283 (Part II), K. S. Salu, J. M. Bosmans, H. Bult and C. J. Vrints,Acta Cardiol 59 (2004) 51.

Examples of antithrombin agents include, but are not limited to, Heparin(including low molecular heparin), R-Hirudin, Hirulog, Argatroban,Efegatran, Tick anticoagulant peptide, and Ppack.

Examples of antiproliferative agents include, but are not limited to,Paclitaxel (Taxol), QP-2, Vincristin, Methotrexat, Angiopeptin,Mitomycin, BCP 678, Antisense c-myc, ABT 578, Actinomycin-D, RestenASE,1-Chlor-deoxyadenosin, PCNA Ribozym, and Celecoxib.

Examples of anti-restenosis agents include, but are not limited to,immunomodulators such as Sirolimus (Rapamycin), Tacrolimus, Biorest,Mizoribin, Cyclosporin, Interferon γ1b, Leflunomid, Tranilast,Corticosteroide, Mycophenolic acid and Biphosphonate. A preferredanti-restenosis agent is Sirolimus.

Examples of anti-migratory agents and extracellular matrix modulatorsinclude, but are not limited to, Halofuginone,Propyl-hydroxylase-Inhibitors, C-Proteinase-Inhibitors, MMP-Inhibitors,Batimastat, Probucol.

Examples of antiplatelet agents include, but are not limited to,heparin.

Examples of wound healing agents and endothelialization promotersinclude vascular epithelial growth factor (“VEGF”), 17β-Estradiol,Tkase-Inhibitors, BCP 671, Statins, nitric oxide (“NO”)-Donors, andendothelial progenitor cell (“EPC”)-antibodies.

Besides coronary applications, drugs and active agents may beincorporated into the stent or stent coating for other indications. Forexample, in urological applications, antibiotic agents may beincorporated into the stent or stent coating for the prevention ofinfection. In gastroenterological and urological applications, activeagents may be incorporated into the stent or stent coating for the localtreatment of carcinoma.

It may also be advantageous to incorporate in or on the stent a contrastagent, radiopaque markers, or other additives to allow the stent to beimaged in vivo for tracking, positioning, and other purposes. Suchadditives could be added to the absorbable composition used to make thestent or stent coating, or absorbed into, melted onto, or sprayed ontothe surface of part or all of the stent. Preferred additives for thispurpose include silver, iodine and iodine labeled compounds, bariumsulfate, gadolinium oxide, bismuth derivatives, zirconium dioxide,cadmium, tungsten, gold, tantalum, bismuth, platinum, iridium, andrhodium. These additives may be, but are not limited to, micro- ornano-sized particles or nano particles. Radio-opacity may be determinedby fluoroscopy or by x-ray analysis.

The concentration of the one or more therapeutic, prophylactic, and/ordiagnostic agents can be readily determined by the attending physicianor surgeon. In one embodiment, the concentration of the drug in the basecoat is about 2 μg/mm².

III. Methods of Making Absorbable Stents

The stents described herein can be fabricated from solution processes,such as dip coating and casting, melt processes such as extrusion andinjection molding, and combinations thereof.

In a preferred method, an absorbable stent may be prepared as follows. Apolymer, such as P4HB or copolymer thereof is optionally mixed in apredetermined ratio with a second absorbable polymer, such as PLLA, andif desired, a plasticizer, such as triethylcitrate (TEC), and/or otheradditives, in a suitable solvent, to prepare a viscous solution of apredetermined concentration. A rod or mandrel of predetermined diameteris then repeatedly dipped into the viscous solution and removed so as tobuild up layers of the absorbable material composition on the rod, byprecipitation of the material as the solvent is evaporated, with thelayer previously deposited only being partially dissolved. Successivedipping of the rod is repeated until the desired thickness of materialis built up on the rod, whereupon the rod is withdrawn to yield acircular tube, known as the stent blank, that may be trimmed or coatedfurther as desired.

In an alternative method to prepare the stent blank, a tube ofpredefined dimensions may be melt extruded from a blend of P4HB orcopolymers thereof, optionally with a second absorbable polymer, such asPLLA, and if desired a plasticizer, and/or other additives.

In a further alternative method to prepare the stent blank, a tube ofpredefined dimensions may be injection molded or micro system injectionmolded from a blend or composition of P4HB or copolymer thereof with thesecond absorbable polymer, such as PLLA, and if desired a plasticizer,and/or other additives.

In a preferred method, the dimensions of the stent blank for coronaryapplication are an external diameter of approximately 1.3 mm, and a wallthickness of approximately 150 μm.

The stent blank may then be cut to form the stent. In a preferredmethod, the stent is cut with a laser according to a predefined stentdesign. Examples of suitable stent designs are described by Grabow etal. (J Biomech Eng. 2005 Feb; 127(1):25-31) and Sternberg et al.(Urologe A. 2004 Oct; 43(10):1200-7). In a preferred embodiment a CO₂laser, Excimer laser, or a femtosecond laser is used to cut the stentblank.

Another alternative method to prepare the stent blank, is to prepare afiber by injection molding or extrusion of a composition of P4HB orcopolymer thereof, optionally with a second absorbable polymer, such asPLLA, and if desired, a plasticizer and /or other additives. The fibermay be reinforced by solid-state drawing. The stent can then befabricated from a single fiber or multiple fibers, which may be wound,knitted, braided, woven or welded to a tubular structure or to form atubular structure.

Additives may, if desired, be added to the stent or stent blank atdifferent steps of the fabrication process. Such additives can includeradiopaque materials and/or active agents.

Also, stent coatings may be added to the stent after stent fabrication.Such coatings can include radiopaque materials and/or active agents.

Absorbable stents prepared according to these methods are characterizedby the following properties; biocompatibility; potentially reduced riskof late stage thrombosis and restenosis; low profile; rapid deploymentin vivo; maintenance of structural integrity after expansion; radialstrength and strength retention; limited recoil after deployment;resistance to creep; elimination of struts that could potentiallyfracture over the long-term; radio-opaque, if desired; good compliancematch between stent and vessel wall; flexibility and low profile topermit delivery of the stent through small vessels and along restrictedand tortuous paths; ability to load drug of choice; ability topositively remodel the vessel wall for long-term patency; compatibilitywith imaging systems, such as CT and MRI; maintenance of length uponexpansion; compatibility with several sterilization options, includinggamma-irradiation, electron beam irradiation, and treatment withethylene oxide; degradation that can include, but is not limited to,surface erosion in addition to bulk degradation; lower aciditydegradation products and, ability to dilate the stent in vivosufficiently quickly to allow the deployment of the stent without riskto the patient, and using only a reasonable amount of pressure.

It is notable in particular that absorbable stents and stent coatingscan be plastically deformed at normal body temperature, and inreasonable operative times (for example, less than 5 minutes and morepreferably less than 1 minute). They do not require the use ofthermo-mechanical expansion or stent designs that rely on the use ofnon-plastic deformation of the stent. For example, U.S. Pat. No.5,670,161 to Healy et al. describes biodegradable stents made fromcopolymers of L-lactide and caprolactone that are not plasticallyexpandable at normal body temperature, but can be expanded by usingthermo-mechanical expansion. Attempting to expand these stents (andother stents made from compositions of degradable materials that are notplastically expandable) in one minute or less causes the stents tofracture. Although not wishing to be bound by theory, this may be due tothe brittle or glassy characteristics of the stent composition. Tamai etal. Circulation, 2000; (102) 399-404 also describes the need to heat aPLLA stent (the Igaki-Tarnai stent) to 50° C. in order to expand thestent in 13 seconds. At normal body temperature, expansion is reportedto take 20 minutes. Zeltinger et al. Biomaterials Forum, 2004 FirstQuarter, 8, 9 and 24, reported that the expansion of absorbable stents,prepared for example from polylactides (poly-L-lactic acid), with theuse of a heated balloon, represented additional risks to the patient,and reported that these stents have therefore not been commercialized.In one approach to overcome the inability to plastically expand stiff,rigid absorbable polymers, this group employed a new stent design, basedupon a slide and lock ratchet mechanism. Thus, prior approaches todeveloping absorbable stents have sought ways using heat to expandrigid, stiff absorbable polymers or polymer compositions or to eliminatethe need for plastic deformation of the polymer composition by usingstent designs, such as slide and ratchet or self-expanding designs thatdo not require compositions that are plastically expandable. Incontrast, the stents made from the compositions described herein can beexpanded without the use of heat.

The specific compositions described herein are highly advantageous inpermitting the deployment of the stent in vivo for coronary applicationsin approximately one minute, using a reasonable inflation pressure andat normal body temperature, yet still providing an absorbable stent withhigh radial strength and strength retention, acceptable recoil andcreep, flexibility to contour to the vessel wall, ability to remodel thevessel wall and degrade over time, and all based upon a low profiledesign. The specific compositions described herein can be designed todegrade more rapidly than stents made from polymers or copolymerscomprising lactic acid. For example, Ormiston et al. (CatheterCardiovasc. Interv. 2006; (69) 128-131) has reported that absorbablestents made from poly-L-lactic acid (PLLA) degrade very slowly over aperiod of 2-3 years. In contrast, a specific composition describedherein of PLLA comprising 22% P4HB (TephaFLEX® biomaterial from Tepha,Inc.) can be fabricated into an absorbable stent that degrades muchfaster. At 48 weeks, less than 20% of the original molecular weight ofthis blend remains compared to almost 50% for a PLLA-derived stent. Therate of degradation may be further adjusted by manipulation of thepercentage of P4HB in the P4HB/PLLA blend.

IV. Method of Coating a Stent with An Absorbable Polymer Composition

In a preferred method, a stent may be coated with an absorbable polymeras follows. A polymer, such as P4HB or copolymer thereof, which mayoptionally incorporate a second absorbable polymer and/or additives, isdissolved at a known concentration in a volatile solvent. The solutionis then sprayed onto the stent to be coated in a uniform manner toprovide an even surface coating of the stent. Evaporation of the solventproduces a film coating on the surface of the stent. The process may berepeated to build up the thickness of the coating. The concentration ofthe solution, application time, drying time, position and rotation ofthe stent, and number of applications, may be adjusted to create thedesired coating thickness, and also to yield a coated stent where thecoating only evenly coats the struts, and does not form web structuresbetween struts. Additionally, dip coating or whirl sintering methods maybe used to apply the coating. The stent may be a metallic stent or astent formed from another material, such as one or polymers, copolymers,terpolymers, polymer blends, or combinations thereof.

Stents coated according to these methods are characterized by thefollowing properties: good biocompatibility; a uniform coating that ismaintained upon expansion of the stent, adheres well to the stentsurface and does not delaminate or crack upon expansion; a coating thatdegrades partly by surface erosion, in addition to bulk erosion, and isthus less likely to cause thrombosis as a result of small fragments ofcoating being released from the stent surface; a coating that is lesslikely to cause an inflammatory response; a coating that can be loadedwith a drug or is compatible with surface coating by a drug; and a stentcoating that can be sterilized by irradiation or treatment with ethyleneoxide.

Due to the ductility and high elongation to break of P4HB, andcopolymers thereof, stent coatings derived from these materials, andapplied using the methods described herein, form exceptionally goodcoatings that maintain their structural integrity after stent expansion,as evidenced by SEM (Scanning Electron Microscopy). This is advantageouswhen compared to more brittle materials of limited ductility and lowelongation to break.

V. Stent Deployment

The stents described herein can be deployed in vivo by any meansappropriate to their design, such as self-expansion, a combination ofself-expansion and balloon-expansion, or balloon-expansion withoutself-expansion. A preferred method of delivery is to mount the stentonto a balloon catheter, insert the stent system into the body at thedesired position for delivery, and expand the balloon in a pressurerange of 4 to 16 bar, more preferably 8 bar, to locate the stent againstthe luminal wall in the desired position.

Due to the greater flexibility, relatively low profile, and smalldiameter of the absorbable stents described herein, it may be possibleto deploy these stents in positions that require navigation of difficultand narrow paths. The stents may be used for coronary, peripheral,urological, gastroenterological, neurological, esophageal and trachealapplications.

The present invention will be further understood by reference to thefollowing non-limiting examples.

EXAMPLES Example 1 Absorbable Coronary Stent from a Dip-Coated StentBlank

Polymer tubes with an inner diameter of 1.0 or 1.4 mm were fabricated bydip-coating of stainless steel male cores into a 2% w/w solution of apreferred composition of 70% PLLA (Resomer® L214 from BoehringerIngelheim Pharma), 20% P4HB (TephaFLEX® biomaterial from Tepha Inc., Mw300-600K) and 10% TEC in chloroform. The dip-coating procedure wasrepeated until a mean wall thickness of 160±10 μm of the polymer tubeswas achieved. Afterwards, the polymer tubes were removed from the coresand washed twice in methanol and twice in water for 24 h each forsolvent removal.

The polymer tubes were then machined with a CO₂ laser for themanufacture of balloon-expandable coronary stents with nominaldimensions in the dilated state of 3.0 and 3.5 mm diameter and variouslengths from 10-25 mm, as established by SEM.

The stents were deployed with a balloon catheter that was inflated to 8bar within 1 minute. The stents exhibited a recoil between 2-10% uponballoon deflation and a collapse pressure of 0.3-0.7 bar. In contrast toother material compositions, such as a composition of P3HB, P4HB andTEC, no strut cracking was observed, as established by comparingdetailed electron micrographs of struts of an absorbable polymeric stentmade from a blend of poly-3-hydroxybutyrate (P3HB),poly-4-hydroxybutyrate (P4HB) and triethylcitrate (TEC) (70/20/10%w/w/w) and from a blend of PLLA, P4HB and TEC (70/20/10% w/w/w) afterdeployment. In contrast to the P3HB/P4HB/TEC stent, the PLLA/P4HB/TECstent exhibits no strut cracking. SEM shows cracking of a stentcomposition of P3HB, P4HB and TEC dilated slowly over 7 minutes,compared to a P4HB, PLLA and TEC composition dilated much more rapidly(in 1 minute) which shows no cracking.

Example 2 Absorbable Coronary Stent From An Extruded Stent Blank

Polymer tubes with an inner diameter of 1.0 or 1.4 mm and a wallthickness of 150 μm were fabricated by extrusion of a preferredcomposition of 78% PLLA (Resomer® L214 from Boehringer Ingelheim Pharma)and 22% P4HB (TephaFLEX® biomaterial from Tepha Inc., Mw 300-600K).

The polymer tubes were then machined with a CO₂ or excimer laser for themanufacture of balloon-expandable coronary stents with nominaldimensions in the dilated state of 3.0 and 3.5 mm diameter and variouslengths from 10-25 mm.

Example 3 Absorbable Polymeric Matrix for a Drug-Eluting Stent Coating

A 0.3% w/w solution of P4HB (TephaFLEX® biomaterial from Tepha, Inc., Mw300-600K) in chloroform was prepared. Metallic coronary stents werespray-coated with this solution until a mean coating layer thickness of15-20 micrometer was achieved. After 24 h storage under vacuum to removethe chloroform, the stents were mounted on standard balloon cathetersand afterwards deployed to a nominal diameter of 3.5 mm. Detailedelectron micrographs of metallic stent struts coated with P4HB beforeand after stent dilation illustrate the smoothness and integrity of thecoating before and after balloon expansion.

Example 4 Permanent Drug-Eluting Stent with Absorbable Polymeric CoatingMatrix and Incorporated Antiproliferative Immunosuppressant (Low Dose)

A 0.3% w/w solution of P4HB (TephaFLEX® biomaterial from Tepha, Inc., Mw300-600K) and rapamycin (70/30% w/w, polymer/drug) in chloroform wasprepared. Metallic coronary stents were spray-coated with this solutionuntil a mean coating layer thickness of 15-20 micrometer was achieved.After 24 h storage under vacuum to remove the chloroform, the stentswere mounted on standard balloon catheters and afterwards deployed to anominal diameter of 3.5 mm. Rapamycin as the active agent was releasedfrom the coating.

Example 5 Permanent Drug-Eluting Stent with Absorbable Polymeric CoatingMatrix and Incorporated Antiproliferative Immunosuppressant (High Dose)

A 0.3% w/w solution of P4HB (TephaFLEX® biomaterial from Tepha, Inc., Mw300-600K) and rapamycin (40/60% w/w, polymer/drug) in chloroform wasprepared. Metallic coronary stents were spray-coated with this solutionuntil a mean coating layer thickness of 15-20 micrometer was achieved.After 24 h storage under vacuum to remove the chloroform, the stentswere mounted on standard balloon catheters and afterwards deployed to anominal diameter of 3.5 mm. Rapamycin as the active agent was releasedfrom the coating.

Example 6 Absorbable Drug-Eluting Stent with IncorporatedAntiproliferative Immunosuppressant (Low Dose)

Polymer tubes with an inner diameter of 2.8 mm were fabricated bydip-coating of stainless steel male cores into a 2% w/w solution of apreferred composition of 70% PLLA (Resomer® L214 from BoehringerIngelheim Pharma), 20% P4HB (TephaFLEX® biomaterial from Tepha Inc., Mw300-600K) and 10% TEC in chloroform. The dip-coating procedure wasrepeated until a mean wall thickness of 250±20 μm of the polymer tubeswas achieved. Afterwards, the polymer tubes were removed from the coresand washed twice in methanol and twice in water for 24 h each forsolvent and TEC removal.

The polymer tubes were then machined with a CO₂ laser for themanufacture of balloon-expandable peripheral vascular stents withnominal dimensions in the dilated state of 6.0 mm diameter and variouslengths from 15-25 mm.

The stents were then spray-coated with a 0.3% w/w solution of P4HB andrapamycin (70:30% w/w, polymer/drug) in chloroform. After 24 h storageunder vacuum to remove the chloroform, the stents were mounted onballoon catheters. The stents were deployed to a nominal I.D. of 6.0 mmwith a balloon catheter, which was inflated to 8 bar within 1 minute.The stents exhibited a recoil of approximately 5% upon balloon deflationand a collapse pressure greater than 0.6 bar. Rapamycin as the activeagent was released from the coating.

Example 7 Absorbable Drug-Eluting Stent with IncorporatedAntiproliferative Immunosuppressant (High Dose)

Polymer tubes with an inner diameter of 2.8 mm were fabricated bydip-coating of stainless steel male cores into a 2% w/w solution of apreferred composition of 70% PLLA (Resomer® L214 from BoehringerIngelheim Pharma), 20% P4HB (TephaFLEX® biomaterial from Tepha Inc., Mw300-600K) and 10% TEC in chloroform. The dip-coating procedure wasrepeated until a mean wall thickness of 250±20 μm of the polymer tubeswas achieved. Afterwards, the polymer tubes were removed from the coresand washed twice in methanol and twice in water for 24 h each forsolvent and TEC removal.

The polymer tubes were then machined with a CO₂ laser for themanufacture of balloon-expandable peripheral vascular stents withnominal dimensions in the dilated state of 6.0 mm diameter and variouslengths from 15-25 mm.

The stents were then spray-coated with a 0.3% w/w solution of P4HB andrapamycin (40/60% w/w, polymer/drug) in chloroform. After 24 h storageunder vacuum to remove the chloroform, the stents were mounted onballoon catheters. The stents were deployed to a nominal I.D. of 6.0 mmwith a balloon catheter which was inflated to 8 bar within 1 minute. Thestents exhibited a recoil of approximately 5% upon balloon deflation anda collapse pressure greater than 0.6 bar. Rapamycin as the active agentwas released from the coating by diffusion and also supported by thepolymer degradation.

Example 8 Accelerated In Vitro Degradation Behavior of an AbsorbablePeripheral Stent from a Polymer Blend Material of High Molecular WeightPLLA and P4HB

Balloon-expandable absorbable peripheral stents with nominal dimensionsin the dilated state of 6.0 mm×25 mm were manufactured from a polymerblend of high molecular weight PLLA (Resomer®® L214 from BoehringerIngelheim Pharma), and P4HB (TephaFLEX® biomaterial from Tepha Inc., Mw300-600K) with a mass ratio of 78/22% or from pure high molecular weightPLLA (Resomert L214). The stents were deployed with balloon cathetersand then incubated in vitro in Sorensen buffer solution at 37° C. toevaluate hydrolytic degradation in vitro.

After 0/2/4/8/12/24/48 weeks, stents were removed from storage andanalyzed by gel permeation chromatography (GPC) to determine molecularweight. FIG. 3 shows the accelerated decrease of molecular weight of thepolymer blend material of high molecular weight PLLA and P4MB incomparison to pure PLLA.

Example 9 In Vitro Drug Release Kinetics of Permanent Drug-ElutingStents with Absorbable Polymeric Coating Matrix and IncorporatedAntiproliferative Immunosuppressant Rapamycin Showing the Influence ofBase Coat Thickness, and of Top Coat Thickness on the Release Profile

A 0.3% w/w solution of P4HB (TephaFLEX® Biomaterial from Tepha, Inc., Mw300-600K) and the immunomodulator rapamycin of 85:15% w/w in chloroformwas prepared. Metallic coronary stents were spray-coated with thissolution as a base coat, until a coating layer thickness of 10-20micrometer was achieved, which is equivalent to a drug content of 1-2 μgper mm² of stent surface area. The stents were then spray-coated with a0.3% w/w solution of P4HB until a top-coat thickness of 5-15 micrometerwas achieved in order to establish different diffusion barriers forretarded drug release. After 24 h storage in vacuo to remove thechloroform, the stents were mounted on standard balloon catheters andafterwards deployed to a nominal diameter of 3.5 mm. The stents werethen stored in 2 ml of a 0.9% sodium chloride solution and incubated at37° C. After different time points, aliquots were taken from the elutionmedium for analysis of released drug, the elution medium was changed,and the stents were put back to storage. The aliquots were analyzed byHPLC.

FIG. 4 displays the in vitro drug release profiles of sample stents,showing the effect of top coat and base coat thicknesses on the drugrelease profile at a constant drug concentration. The use of a top-coatretarded the drug release (stent 85:15-1 compared to stent 85:15-2). Theuse of a thicker top-coat retarded the drug release further (stents85:15-1 and 85:15-2 compared to stent 85:15-3). The use of a thinnerbase coat reduces the amount of drug released (stent 85:15-1 compared tostent 85:15-4).

Example 10 In Vitro Drug Release Kinetics of Permanent Drug-ElutingStents with Absorbable Polymeric Coating Matrix and IncorporatedAntiproliferative Immunosuppressant Rapamycin Showing the Influence ofDrug Content, and of Base Coat Thickness on the Release Profile

A 0.3% w/w solution of P4HB (TephaFLEX® biomaterial from Tepha, Inc., Mw300-600K) and the immunomodulator rapamycin of 85:15% w/w(polymer/drug), or 70:30% w/w, or 40:60% w/w in chloroform was prepared.Metallic coronary stents were spray-coated with either of thesesolutions as a base coat, until a coating layer thickness of 5-10micrometer was achieved, which is equivalent to a drug content of 1-2 μgper mm² of stent surface area. The stents were then spray-coated with a0.3% w/w solution of P4MB until a top coat thickness of 10 micrometerwas achieved in order to establish a diffusion barrier to retard drugrelease. After 24 h storage in vacuo to remove the chloroform, thestents were mounted on standard balloon catheters and afterwardsdeployed to a nominal diameter of 3.5 mm. The stents were then stored in2 ml of a 0.9% sodium chloride solution and incubated at 37° C. Afterdifferent time points, aliquots were taken from the elution medium, theelution medium was changed, and the stents were put back to storage. Thealiquots were analyzed by HPLC.

FIG. 5 displays in vitro drug release profiles of sample stents, showingthe increasing drug release at higher drug concentrations at a constanttop-coat thickness. The elution rate and the total amount of drugreleased increases as the concentration of drug in the basecoat coatincreases (stent 85:15-4 compared to stent 70:30-1 and stent 40:60-1).

Example 11 Safe Mounting of an Absorbable Coronary Stent onto a BalloonCatheter

Balloon-expandable absorbable stents with an inner diameter of 1.4 mm inthe undilated state and a length of 10 mm were manufactured from apolymer blend of high molecular weight PLLA and P4HB (TephaFLEX®biomaterial from Tepha, Inc., Mw 300-600K) by melt extrusion followed bylaser cutting. The polymeric stents were mounted without crimping ondedicated balloon catheter systems with nominal dimension of 3.5 mm×10mm in the dilated state. The balloon catheter system contained an innersupport tube in the balloon region underneath the stent to enhance stentretention. The inner support tubing was made from an elastomericmaterial and provided an interference fit to hold the mounted stent inplace. The diameter or durometer of the elastic support tubing could bemodified to adjust the resistance of the interference fit and modify thestent retention. The dislodgment force of the stent systems were testedusing a universal testing machine.

A mean stent dislodgement force of 2 N, and a maximum dislodgement forceof greater than 5 N were measured. Without the inner support tubing, thedislodgment force was less than 0.3 N and would not be suitable forintravascular deployment without some method to hold the stent in place.

Example 12 In Vitro Drug Release Kinetics of Permanent Drug-ElutingStents with Absorbable Polymer Blend Coating Matrices and IncorporatedAnti-Proliferative Immunosuppressant Rapamycin (Sirolimus) Showing theEffect of Base Coat Blend Ratio on the Release Profile

Solutions with a concentration of 0.3% w/w P(4HB)/PLLA/Sirolimus inchloroform were prepared with a polymer/sirolimus ratio of 85/15 w/w andP(4HB)/PLLA blend ratios of 100/0, 70/30, 50/50, and 30/70 w/w. Metalliccoronary stents were spraycoated with the solutions as a base coat untila mean coating layer thickness of 20 microns, which is equivalent to 2μg/mm². was obtained. The stents were then spraycoated with a 0.3% w/wdrug-free solution of P(4HB) until a mean top coat thickness of 15microns was obtained. The stents were stored for 24 hours in vacuo at25° C. to remove residual chloroform. The stents were mounted onstandard balloon catheters and expanded to a nominal diameter of 3.0 mm.The stents were then stored in 2 ml of a 0.9% sodium chloride solutionand incubated at 37° C. At different time points, aliquots were takenfrom the elution medium, the elution medium replaced, and the stentsreturned to the new elution medium. The aliquots were analyzed by HPLC.The results are shown in FIG. 6. FIG. 6 shows the in vitro drug releaseprofiles for a variety of stents. Increasing the concentration of PLLAin the base increasingly retarded release of the drug.

Example 13 In Vitro Drug Release Kinetics of Permanent Drug-ElutingStents with Absorbable Polymer Blend Coating Matrices and IncorporatedAnti-Proliferative Immunosuppressant Rapamycin (Sirolimus) Showing theEffect of the Top Coat Blend Ratio on the Release Profile

Solutions with a concentration of 0.3% w/w P(4HB)/PLLA/Sirolimus inchloroform were prepared with a polymer/sirolimus ratio of 85/15 w/w andP(4HB)/PLLA blend ratios of 100/0, 70/30, 50/50, and 30/70 w/w. Metalliccoronary stents were spray-coated with the solutions as a base coatuntil a mean coating layer thickness of 20 microns, which is equivalentto 2 μg/mm². was obtained. The stents were then spray-coated with a 0.3%w/w drug-free solution of the same P(4HB)/PLLA blend as the base coatuntil a mean top coat thickness of 15 microns was obtained. The stentswere stored for 24 hours in vacuo at 25° C. to remove residualchloroform. The stents were mounted on standard balloon catheters andexpanded to a nominal diameter of 3.0 mm. The stents were then stored in2 ml of a 0.9% sodium chloride solution and incubated at 37° C. Atdifferent time points, aliquots were taken from the elution medium, theelution medium replaced, and the stents returned to the new elutionmedium. The aliquots were analyzed by HPLC. The results are shown inFIG. 7. FIG. 7 shows the in vitro drug release profiles for a variety ofstents. The addition of PLLA to the top coat retarded release of thedrug compared to P(4HB) alone.

Example 14 Improved Coating Integrity of Permanent Drug Eluting Stentswith Absorbable Polymer Blend Coating Matrices

Solutions with a concentration of 0.3% w/w P(4HB)/PLLA in chloroformwere prepared with the following P(4HB)/PLLA blend ratios: 5/95, 10/90,and 20/80% w/w. Metallic coronary stents were spray-coated with thesolutions, until a mean coating layer thickness of 20 micrometer wasachieved. After 12 h storage at 60° C. in vacuo to remove thechloroform, the stents were mounted on standard balloon catheters,beta-sterilized, and expanded to a nominal diameter of 3.0 mm.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. An absorbable biocompatible stent comprising a blend ofpoly-4-hydroxybutyrate (P(4HB)) and poly(L-lactide) (PLLA) comprisingbetween 5 and 95% P4HB by weight of the polylactide, wherein the stentis expandable at normal body temperature, and is of a first diametersufficient to be retained upon a balloon catheter for placement within abody lumen, and is expandable to a second diameter sufficient to beretained within the body lumen.
 2. . The stent of claim 1, wherein theratio of P(4HB) to PLLA in the blend is selected from the groupconsisting of 95/5 P(4HB)/PLLA w/w, 90/10 P(4HB)/PLLA w/w, 85/15P(4HB)/PLLA w/w, 80/20 P(4HB)/PLLA w/w, 75/25 P(4HB)/PLLA w/w, 70/30P(4HB)/PLLA w/w, 65/35 P(4HB)/PLLA w/w, 60/40 P(4HB)/PLLA w/w, 55/45P(4HB)/PLLA w/w, 50/50 P(4HB)/PLLA w/w, 45/55 P(4HB)/PLLA w/w, 40/60P(4HB)/PLLA w/w, 35/65 P(4HB)/PLLA w/w, 30/70 P(4HB)/PLLA w/w, and 22/78P(4HB)/PLLA w/w.
 3. The stent of claim 1, wherein the ratio of P(4HB) toPLLA in the blend is between 95/5 P(4HB)/PLLA w/w and 22/78 P(4HB)/PLLAw/w.
 4. The stent of claim 1, wherein the stent further comprises one ormore therapeutic, diagnostic or prophylactic agents is selected from thegroup consisting of anti-inflammatory agents, immunomodulators,antithrombin agents, anti-proliferative agents, anti-restenosis agents,anti-migratory agents, extracellular matrix modulators, antiplateletagents, wound healing agents, endothelialization promoters, andcombinations thereof.
 5. The stent of claim 4, wherein the one or moretherapeutic, diagnostic or prophylactic agents is an anti-restenosisagent selected from the group consisting of Sirolimus (Rapamycin),Tacrolimus, Biorest, Mizoribin, Cyclosporin, Interferon lb, Leflunomid,Tranilast, Corticosteroide, Mycophenolic acid, Biphosphonate, andcombinations thereof.
 6. The stent of claim 5, wherein theanti-restenosis agent is rapamycin.
 7. A biocompatible stent comprisinga base coat and optionally a top coat, wherein the base coat comprises ablend of P(4HB) and PLLA and one more therapeutic, diagnostic orprophylactic agents, wherein the ratio of P(4HB) to PLLA in the blend isselected from the group consisting of 95/5 P(4HB)/PLLA w/w, 90/10P(4HB)/PLLA w/w, 85/15 P(4HB)/PLLA w/w, 80/20 P(4HB)/PLLA w/w, 75/25P(4HB)/PLLA w/w, 70/30 P(4HB)/PLLA w/w, 65/35 P(4HB)/PLLA w/w, 60/40P(4HB)/PLLA w/w, 55/45 P(4HB)/PLLA w/w, 50/50 P(4HB)/PLLA w/w, 45/55P(4HB)/PLLA w/w, 40/60 P(4HB)/PLLA w/w, 35/65 P(4HB)/PLLA w/w, 30/70P(4HB)/PLLA w/w, and 22/78 P(4HB)/PLLA w/w.
 8. A biocompatible stentcomprising a base coat and optionally a top coat, wherein the base coatcomprises a blend of P(4HB) and PLLA and one more therapeutic,diagnostic or prophylactic agents, wherein the ratio of P(4HB) to PLLAin the blend is between 85/15 P(4HB)/PLLA w/w and 22/78 P(4HB)/PLLA w/w.9. The stent of claim 8, wherein the top coat is substantially free ofone or more therapeutic, diagnostic, or prophylactic agents.
 10. Thestent of claim 8, wherein the base coat, top coat, or combinationsthereof further comprise a plasticizer.
 11. The stent of claim 10,wherein the concentration of the plasticizer is from about 0 to 10% byweight of the coating.
 12. The stent of claim 10, wherein theplasticizer is triethylcitrate.
 13. The stent of claim 8, wherein thestent is selected from the group consisting of a metallic stent and apolymeric stent, wherein the stent is expandable at normal bodytemperature, and is of a first diameter sufficient to be retained upon aballoon catheter for placement within a body lumen, and is expandable toa second diameter sufficient to be retained within the body lumen. 14.The stent of claim 8, wherein the stent has improved surface integritycompared to a coating containing only PLLA.
 15. The stent of claim 13,wherein the base coat, top coat, or combinations thereof, degrade inless than two years, more preferably in less than one year, and mostpreferably in less than six months.
 16. A method of making the stent ofclaim 8, the method comprising coating a stent with a base coatcomprising a blend of P(4HB), PLLA, and one or more therapeutic,diagnostic, or prophylactic agents, and optionally coating the base coatwith a top coat.
 17. A method of deploying the stent of claim 1,comprising mounting the stent on a delivery system and balloon-expandingthe stent inside the body lumen.
 18. The stent of claim 13, wherein thebase coat has a thickness of from about 10 microns to about 50 microns.19. The stent of claim 18, wherein the base coat has a thickness of fromabout 15 microns to about 25 microns.
 20. The stent of claim 18, whereinthe base coat has a thickness of about 10 to 20 microns.
 21. The stentof claim 13, wherein the one or more therapeutic, diagnostic orprophylactic agents is selected from the group consisting ofanti-inflammatory agents, immunomodulators, antithrombin agents,anti-proliferative agents, anti-restenosis agents, anti-migratoryagents, extracellular matrix modulators, antiplatelet agents, woundhealing agents, endothelialization promoters, and combinations thereof.22. The stent of claim 21, wherein the concentration of the drug in thebase coat is about 2 μg/mm².
 23. The stent of claim 13, wherein the oneor more therapeutic, diagnostic or prophylactic agents is ananti-restenosis agent selected from the group consisting of Sirolimus(Rapamycin), Tacrolimus, Biorest, Mizoribin, Cyclosporin, Interferonγ1b, Leflunomid, Tranilast, Corticosteroide, Mycophenolic acid,Biphosphonate, and combinations thereof.
 24. The stent of claim 22,wherein the anti-restenosis agent is rapamycin.
 25. The stent of claim13, further comprising a top coat, wherein the top coat comprisesP(4HB).